features of the disorder (6). That risk for suicide attempt in particular is heritable is supported by twin studies (7, 8), with heritability estimates ranging from ...
Article
Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients Roy H. Perlis, M.D., M.Sc.
Markus Nöthen, Ph.D.
Jie Huang, M.D., M.S., M.P.H.
Sven Cichon, Ph.D.
Shaun Purcell, Ph.D.
Hugh Gurling, M.D., M.Phil.
Maurizio Fava, M.D.
Nick Bass, M.D.
A. John Rush, M.D.
Andrew McQuillin, Ph.D.
Patrick F. Sullivan, M.D.
Marian Hamshere, Ph.D.
Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts.
Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety.
Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement
Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
Francis J. McMahon, M.D.
Wellcome Trust Case Control Consortium Bipolar Disorder Group
Thomas Schulze, M.D.
Nick Craddock, M.D., Ph.D.
James B. Potash, M.D., M.P.H.
Pamela Sklar, M.D., Ph.D.
Steven P. Hamilton, M.D., Ph.D.
Jordan W. Smoller, M.D., Sc.D.
Peter P. Zandi, Ph.D. Virginia L. Willour, Ph.D. Brenda W. Penninx, Ph.D., M.D. Dorret I. Boomsma, Ph.D. Nicole Vogelzangs, Ph.D. Christel M. Middeldorp, M.D., Ph.D. Marcella Rietschel, M.D.
Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort.
(Am J Psychiatry 2010; 167:1499–1507)
E
pidemiologic studies indicate that mood disorders are associated with a marked increase in risk for suicide and suicide attempts, with one such study suggesting a 20-fold greater risk of death from suicide compared with the general population (1). The familiality of suicide risk is well-established (for a review, see Brodsky et al. [2]) and not accounted for solely by familial transmission of mood disorders (3–5). For example, a family-based study of a large, bipolar disorder cohort suggested that lifetime suicide attempts were among the more strongly familial
features of the disorder (6). That risk for suicide attempt in particular is heritable is supported by twin studies (7, 8), with heritability estimates ranging from 30%–50%, intermediate between major depressive disorder and bipolar disorder. Adoption studies suggest that this risk cannot be explained solely by shared environment (9). Individual candidate-gene studies have implicated genes of the serotonergic or noradrenergic system (10–14), hypothalamic-pituitary-adrenal axis (15, 16), renin-angiotensin system (17), and neuronal development (18–20)
This article is discussed in an editorial by Drs. Uher and Perroud (p. 1425) Am J Psychiatry 167:12, December 2010
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SUICIDE ATTEMPTS IN MOOD DISORDER GWAS TABLE 1. Mood Disorder Cohorts Included in Suicide Attempt Analyses Suicide Attempt Disorder Cohort Bipolar disorder Discovery Replication Major depressive disorder Discovery Replication
Study Cohort STEP-BD; Wellcome Trust Case Control Consortium; University College London GAIN bipolar disorder project; Translational Genomics Research Institute; Universities of Bonn/Heidelberg STAR*D Caucasian Netherlands Study of Depression and Anxiety/Netherlands Twin Register
Combined
and function (21) in the propensity for suicide, using a variety of case and control definitions (for a review, see Brezo et al. [22]). However, given the limited understanding of pathophysiology, prioritizing candidates for study has been difficult and likely accounts for the near absence of consistent replication. The emergence of low-cost approaches for characterizing common genetic variation across the genome facilitates an alternate approach, which may lead to identification of truly novel risk factors, as has been the case in nonpsychiatric disorders (23). Therefore, we analyzed data from multiple genomewide association studies to identify variations associated with suicide risk. To minimize the potential heterogeneity introduced by pooling mood disorder subjects, cohorts with bipolar disorder and major depression were examined separately and then combined for meta-analysis. In all, data from >8,700 mood disorder subjects were used to detect and replicate associations.
Method Study Design, Genotyping, Quality Control, and Imputation The cohorts examined in the present study are summarized in Table 1. For bipolar disorder, genomewide association data were derived from three nonoverlapping cohorts of bipolar I or II patients, all of which were included in a previously reported meta-analysis of disease liability (24). These bipolar disorder cohorts were from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) (25, 26), the Wellcome Trust Case Control Consortium (27), and the University College London. Details of sample ascertainment and genotyping have been previously described by Ferreira et al. (24). Quality control and imputation using MACH (28) are described in the original reports (summarized in the data supplement accompanying the online version of this article), yielding 1,922,309 single nucleotide polymorphisms (SNPs) in 3,117 subjects. Follow-up analyses examined the most significant SNPs from these cohorts in pooled data from the following three additional bipolar disorder cohorts: the initial Genetic Association Information Network (GAIN) bipolar disorder project and the Translational Genomics Research Institute samples (29), both drawn from the five waves of sample collection in the NIMH Bipolar Disorder Genetics Initiative (30), and a sample of German individuals collected at the Universities of Bonn and Heidelberg (31).
1500
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N
N
%
3,117
1,295
41.5
2,698
1,201
44.5
1,273 1,649
176 133
9.9 8.1
8,737
2,805
32.1
Genotyping, quality control, and imputation are described by Smith et al. (29) and McMahon et al. (31). Table 1 also lists the major depression cohorts included in primary and replication analyses, which were the Systematic Treatment Alternatives to Relieve Depression (STAR*D) cohort (32) and the GAIN depression cohort that was derived from the Netherlands Study of Depression and Anxiety (33)/Netherlands Twin Register (34) cohorts (35). The former data set was used in initial analyses, with replication pursued in the latter. Details of genotyping and quality control for the STAR*D cohort have been previously described by Garriock et al. (36) (for additional quality control steps and imputation using MACH, see the data supplement), yielding 1,954,455 SNPs in 1,273 subjects. For the Netherlands Study of Depression and Anxiety/Netherlands Twin Register, methods are described by Sullivan et al. (35). Imputation was performed using IMPUTE (http://mathgen.stats.ox.ac. uk/impute/impute.html), with a threshold of 70% confidence.
Identification of Lifetime Suicide Attempts For the STEP-BD cohort, determination of lifetime suicide attempts was conducted using all available sources of information, including the Affective Disorders Evaluation (37), which incorporates questions from the Structured Clinical Interview for DSM-IV Axis I Disorders (38) at study entry, as well as data regarding suicide attempt during the study period documented as serious adverse effect or hospitalization. In the Wellcome Trust Case Control Consortium, lifetime suicide attempts were identified with a semistructured diagnostic psychiatric interview. Assessment of the University College London cohort was conducted utilizing the Schedule for Affective Disorders and Schizophrenia–Lifetime version (39), which includes questions about the presence or absence of lifetime suicide attempt. Among the replication cohorts, the GAIN and Translational Genomics Research Institute samples were assessed using the Diagnostic Interview for Genetic Studies (40), which includes questions regarding lifetime suicide attempt. Assessment of the German university cohorts also incorporated structured interview and review of psychiatric history. In the STAR*D cohort, lifetime history of suicide attempts was assessed at the initial study visit by the study clinician (41); suicidality was not exclusionary, provided the patient did not require hospitalization for stabilization. Finally, lifetime suicide attempt in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register group was determined at diagnostic interview, which included the Composite International Diagnostic Interview, version 2.1 (42).
Analysis Primary analyses were performed with logistic regression of the presence or absence of suicide attempt on single SNP allelic Am J Psychiatry 167:12, December 2010
PERLIS, HUANG, PURCELL, ET AL. TABLE 2. Loci Showing Strongest Evidence of Association With Suicide Attempt in Bipolar Disorder Discovery Cohort Chromosome 3 5 2 8 3
SNP
p
Additional SNPs (p
